Presbyopia treatment by lens alteration

ABSTRACT

This invention effects a change in the accommodation of the human lens affected by presbyopia through the use of various reducing agents that change accommodative abilities of the human lens, and/or by applying energy to affect a change in the accommodative abilities of the human lens. This invention both prevents the onset of presbyopia as well as treats it. By breaking and/or preventing the formation of bonds that adhere lens fibers together causing hardening of the lens, the present invention increases the elasticity and distensibility of the lens and/or lens capsule.

Pursuant to 35 U.S.C. § 120, the present invention claims priority tothe filing date of the provisional application No. 60/264,423 filed Jan.19, 2001 by the above-named inventor. Applicant incorporates herein theprovisional application No. 60/264,423 in its entirety for backgroundinformation.

FIELD OF THE INVENTION

The present invention relates to a method and device for reversing andtreating presbyopia.

BACKGROUND OF THE INVENTION

Presbyopia affects virtually every person over the age of 44. Accordingto Jobson Optical Database, 93% of people 45 and over are presbyopic.Presbyopia entails the progressive loss of amplitude of accommodationthat occurs with aging. Adler's Physiology of the Eye, which isincorporated herein by reference, discloses that the human accommodativeamplitude declines with age such that accommodation is substantiallyeliminated by the age of 50 to 55. Accommodative ability, as defined byU.S. Pat. No. 5,459,133 to Neufeld and incorporated in its entiretyherein by reference for background information, is the capacity of theeye to focus for near vision by changing the shape of the lens to becomemore convex.

The ocular tissues involved in the accommodative response include thelens, the zonules, the lens capsule, and the ciliary muscle. Of these,the lens is the central tissue. These structures function together toenable the eye to focus on close objects by changing the shape of thelens. The lens is centrally suspended between the anterior and posteriorchambers behind the pupillary opening of the iris. The lens is supportedby an array of radially oriented zonular fibers, which extend from thelateral edges of the lens to the inner border of the circumferentialciliary muscle. The ciliary muscle is attached to the scleral coat ofthe eye. When the eye is at rest, it is focused for distance and thelens is in a somewhat flattened or less convex position. This shape isdue to the tension that is exerted on the lens periphery by the zonules.The zonules pull the edges of the lens toward the ciliary body.

During accommodation, the shape of the lens becomes more convex throughcontraction of the ciliary muscle, which allows the ciliary attachmentof the zonules to move toward the lens, reducing the tension in theanterior zonules. This reduction in tension allows the central region ofthe lens to increase in convexity, thereby enabling near objects to beimaged on the retina. The processes involving the coordinated effort ofthe lens, zonules, ciliary body, medial rectus muscles and iris,among-others, that leads to the ability of the eyes to clearly focusnear on the retina is the accommodative process.

Several theories have been advanced to explain the loss of accommodationwith age. These theories include the hardening of the lens with age,loss of strength in the ciliary muscle, factors related to the physicalgrowth of the lens, and, the loss of elasticity of the lens capsule. Asfor the loss of strength of the ciliary muscle, it is noted thatalthough there are age-related morphological changes that occur, thereis little evidence of diminishing strength of the ciliary muscle. Infact, under the influence of pilocarpine, the ciliary muscle willvigorously contract even in presbyopic eyes.

The lens grows throughout one's life and theories have been proposedthat it is this increase in size that prohibits the effects of thezonules from affecting a change in the shape of the lens. Recent worksexploring this possibility have not met widespread acceptance thus far.Most of the growth of the lens is not in its diameter, but instead, inits anterior-posterior dimensions.

As for changes in the lens capsule, it has been postulated thatreduction in the elasticity of the capsule is, in fact, a contributingfactor in presbyopia. Moreover, it has been found that Young's modulusof elasticity for the lens capsule decreases by nearly 50% from youth toage 60, while accommodation decreases by 98%. Consequently, theprincipal cause of presbyopia is now considered to be “lenticularsclerosis” or the hardening of the lens.

A cataract is a condition in which the lens becomes less clear. Thestudy of cataracts lends insight into lens and capsular changes. Theusual senile cataract is relatively discus-shaped when removed from theeye, its shape being dictated by the firm lens substance. The liquefiedhypermature cataract is globular when extracted, rounded up by theelastic lens capsule. This is indirect evidence that it may be possibleto reverse the lenticular changes associated with presbyopia, and thatthe lens capsule is still sufficiently elastic.

At the present time, common treatments for presbyopia include readingglasses, bifocal glasses, or mono-vision contact lenses. All of thesesolutions necessitate the use of an appliance creating additionalshortcomings.

Alternative theories for treating presbyopia include scleral expansionand corneal reshaping. The efficacy of such techniques is notwell-established and, importantly, these techniques do not attempt toreverse what the inventors of the subject-application believe to be asubstantial causation, as explained more fully below, in the loss of theaccommodative amplitude of the lens typically associated with the normalaging process. Moreover, because scleral expansion and corneal reshapinginvolve macroscopic changes in the morphology of the lens and/or corneait fails to reverse presbyopia.

Finally, the use of the excimer laser for the purposes of cornealreshaping to produce a multifocal refracting surface has been disclosedin U.S. Pat. No. 5,395,356. While this method seems promising, it stillrequires structural changes to the cornea to compensate for agingchanges in the lens. Rather than trying to undo the changes brought onby presbyopia, techniques such as these merely compensate for the lossof accommodative function by altering another ocular structure.

SUMMARY OF THE INVENTION

While not wishing to be bound to any particular theory, it is nowbelieved that presbyopia is caused by the hardening of the lens, whichcan be due to an alteration of the structural proteins or an increasedadhesion between the lens fibers. It is also believed that theintralenticular viscosity increases with age as a result of theformation of certain chemical bond structures within the lens.Accordingly, the present invention is directed to method and apparatusfor preventing and or reversing presbyopia through treatment of the lenssuch that the viscosity of the lens is reduced, restoring the elasticityand movement to the lens fibers and increasing the accommodativeamplitude of the lens.

The claimed invention is also directed to a method of reversing ortreating presbyopia resulting in underlying changes in the structuresand/or interactions of molecules comprising those components of the eyeassociated with the accommodative process, most notably the lens and/orlens capsule.

In an embodiment, the present invention provides a novel molecularapproach to reversing presbyopia by restoring the accommodativeamplitude of the lens, and in another preferred embodiment, to reversingpresbyopia while also reducing the tendency for the lens to lose itsthus restored accommodative amplitude.

In another embodiment of the invention the onset of presbyopia isprevented by regularly administered treatment where elasticity and theaccommodative ability of the lens is restored. By applying thetreatments as described herein to the eyes of persons in their mid tolate 30's, or even younger, the on-set of presbyopia, as defined by aloss of accommodation, such that the accommodative power of the eye isbelow 2.5 Diopters, can be avoided. In one embodiment of the invention,such treatments whether for the purposes of preventing or reversingpresbyopia, would be occasionally repeated during the course of apatient's lifetime. The frequency of the treatment would be determinedby the degree of accommodative loss that needs to be recovered, theamount of accommodation that can be safely restored in a singleprocedure, and the amount of restoration desired.

In one embodiment, the present invention is directed to a method forreversing and/or treating presbyopia by breaking disulfide bonds inmolecules comprising the structures of the eye, most notably the lensand the lens capsule, in which disulfide bonds are believed to be asubstantial factor in the progressive loss of accommodative amplitude.In another embodiment, the breaking of the disulfide bonds isaccompanied by chemical modification of the sulfur moiety in thecysteine molecule formed upon breaking of the disulfide bonds, suchchemical modification rendering the sulfur moiety less likely to formnew disulfide bonds. This method thus comprises a method for preventing,and/or reducing the recurrence of presbyopia by reducing the probabilityof forming new disulfide bonds. Particularly, this invention affects achange in the accommodative amplitude of the human lens by: (1) usingvarious reducing agents that cause a change in the accommodativeabilities of the human lens, and/or (2) the use of applied energy toaffect a change in the accommodative abilities of the human lens. It isbelieved that by breaking bonds, such as disulfides, that crosslink lensfibers together and increase lens viscosity causing a hardening of thelens cortex and lens nucleus, the present invention increases theelasticity and the distensibility of the lens cortex, lens nucleus,and/or the lens capsule.

Presbyopia, or the loss of the accommodative amplitude of the lens, hasoften advanced in a typical person age 45 or older to the point wheresome type of corrective lens in the form of reading glasses or othertreatment is required. It is to be understood that loss of accommodativeamplitude can occur in persons much younger or older than the age of 45,thus the present invention is not to be construed as limited to thetreatment of presbyopia in a person of any particular age. The presentinvention is most useful in a person whose accommodative amplitude haslessened to a point where restoration thereof to some degree isdesirable. However the invention should not be limited to the correctionof presbyopia, but may be used to prevent presbyopia from occurring.

In one embodiment of the present invention, the method of reversing orpreventing presbyopia will result in an increase in the accommodativeamplitude at least about by 0.5 diopters. In another embodiment of thepresent invention, the method of reversing or preventing presbyopia willresult in an increase in the accommodative amplitude of at least about2.0 diopters. In still another embodiment, the method of reversing orpreventing presbyopia of the present invention will result in anincrease in the accommodative amplitude by at least about 5 diopters. Inanother embodiment of the present invention, the method of reversing orpreventing presbyopia of the present invention will result in anincrease of the accommodative amplitude of the lens to restorationthereof to that of a lens with a normal accommodative amplitude of 2.5diopters or greater. It is noted that while it is obviously mostbeneficial to restore the accommodative amplitude of the lens to anormal accommodative amplitude, lesser degrees of restoration are alsobeneficial. For example, in some cases advanced presbyopia can causesevere reduction in the accommodative amplitude, thus making a completerestoration of the amplitude improbable.

DETAILED DESCRIPTION

The accommodative amplitude of the lens is measured in diopters (D). Theloss of accommodative ability begins at a very early age, such that byage 10 the average eye has 10 D, age 30, 5D, and by age 40, only 2.5D ofaccommodative power. The lens of a person who does not suffer frompresbyopia. (i.e. a person whose lens accommodates normally), willtypically have an accommodative amplitude of about 2.5 diopters orgreater. The terms “reversing presbyopia” or “treating presbyopia” asused herein mean increasing the accommodative amplitude of the lens.

As stated, inelasticity of the lens, or hardening thereof, is believedto be a contributing cause of presbyopia. The hardening of the lens canbe due to an alteration of the structural proteins or an increasedadhesion between the lens fibers. Additionally, it is believed that thelens viscosity also increases with age due to an increased concentrationof certain chemical bond structures within the lens. In one embodiment,the present invention is directed to treating presbyopia by altering themolecular and/or cellular bonds between the cortical lens fibers so asto free their movement with respect to each other. The increasedelasticity of the lens apparatus can restore lost amplitude ofaccommodation. Specifically, it is believed that disulfide bonds in themolecules comprising the structures of the eye responsible for properaccommodation are a substantial factor in the hardening of the lens andthe concomitant loss of accommodative amplitude.

Thus, in one embodiment of the invention treatment process involvesbreaking the disulfide bond and then protonating the newly formed sulfurmoiety with a reducing agent such as glutathione to impart a hydrogenatom thereto. The steps can be performed simultaneously orconsecutively. In either case, the reducing agent can be present at thetime the disulfide bond is broken in order to eliminate reformation ofdisulfide. That is, the reducing agent can introduce and bond a moietyonto the free sulfur after breaking the disulfide bond such that thelikelihood of reformation of another disulfide bond is prevented or atleast reduced. While the reducing agent may introduce a hydrogen atomonto the free sulfur, thus forming a sulfhydryl group (—SH), theresultant —SH groups can again be oxidized to form a new disulfide bond.Thus, it is advantageous to introduce a group into the free sulfurmoiety such as lower alkyls, methylating compounds, or other agents,which reduce the tendency of new disulfide bond formation. This methodcan result in a substantial prevention of the reoccurrence ofpresbyopia.

As stated, it is believed that the disulfide bonds form both between thelens fibers, between lens proteins, and between lens proteins andvarious thiols both within and on lens fibers. These bonds andsubstantially reduce the lens fibers' ability to easily move relative toeach other and thus the ability of the lens to accommodate properly.While not wishing to be bound by any particular theory, the bonds mayform by way of absorption of light energy, which causes the sulfhydrylbonds on the lens proteins to oxygenate removing a hydrogen atom fromtwo adjacent —SH groups and creating water and a disulfide bond.Reducing the disulfide bonds requires hydrogen donors such asglutathione or other molecules. Other possible theories involveprotein-thiol mixed disulfide bonds forming such asprotein-S—S-glutathione or protein-S—S-cysteine. Glutathione thereforemay be both part of the solution and part of the problem. The use ofGlutathione in any treatment regimen therefore must-be monitoredcarefully in light of the potential for an increase in undesirable bondformation.

The total refractive power of the lens is greater than what would beexpected based on the curvature and the index of refraction. As stated,contraction of the ciliary muscle causes the ciliary body to moveforward and towards the equator of the lens. This causes the zonules torelax their tension on the lens capsule, which allows the central lensto assume a more spherical shape. During accommodation, the main changeis in the more central radius of curvature of the anterior lens surface,which is 12 mm in the unaccommodative state and can be 3 mm centrallyduring accommodation. Both the peripheral anterior and the posteriorlens surfaces change very little in curvature during accommodation. Theaxial thickness increases while the diameter decreases. The centralanterior lens capsule is thinner than the rest of the anterior capsule.This may explain why the lens bulges more centrally duringaccommodation. The thinnest portion of the capsule is the posteriorcapsule, which has a curvature greater than the anterior capsule in theunaccommodative state. The protein content of the lens, almost 33% byweight, is higher than any other organ in the body. There are manychemical compounds of special interest in the lens. For example,glutathione is found in high concentration in the lens cortex eventhough there is very little in the aqueous. Thus, the lens has a greataffinity for glutathione and actively absorbs, transports andsynthesizes glutathione. Approximately 93% of intralenticularglutathione is in the reduced form. Glutathione may be involved withmaintaining the lens proteins, the sulfhydryl groups (—SH), in theirreduced states. That is, after the disulfide bond is broken and thesulfur moieties are made available, glutathione can impart a hydrogenatom to form the sulfhydryl group thereby preventing or minimizing thereformation of a disulfide bond. In addition, ascorbic acid can also befound in very high concentrations in the lens. It is activelytransported out of the aqueous and is at concentrations 15-times thatfound in the bloodstream. Both inositol and taurine are found at highconcentrations in the lens for which the reason is not known.

According to one embodiment of the invention, the increase in theaccommodative amplitude is accomplished by treatment of the outer lensregion (the cortex) or the inner layer (the nucleus) with radiation,sonic or electromagnetic energy, heat, chemical, particle beam, plasmabeam, enzyme, gene therapy, nutrients, other applied energy source,and/or any combination of any of the above sufficient to break thedisulfide bonds believed responsible for the inelasticity of the lens.Chemicals are useful to reduce disulfide bonds that are believed toanchor lens fibers hence preventing their free movement and elasticity.By making the anterior cortex and/or the nucleus more elastic, viscosityis lowered and the lens is again able to assume its characteristiccentral bulge during accommodation.

Chemicals suitable for causing reduction include, by way of exampleonly, glutathione, ascorbic acid, Vitamin E, tetraethylthiuram disulfyl,i.e., reducing agent, any biologically suitable easily oxidizedcompound, ophthalmic acid, inositol, beta-carbolines, any biologicallysuitable reducing compound, reducing thiol derivatives with thestructure:

or sulfur derivatives with the structures:

Wherein R₁, R₂, R₃ and R₄ are independently a straight or branched loweralkyl that may be substituted, e.g., by hydroxyl, lower alkoxy or loweralkyl carbonyloxy, their derivatives or a pharmaceutically acceptablesalt thereof. Preferred exemplary reducing agents include diethyldithiocarbamate, 1-methyl-1H-tetrazol-5-yl-thiol and1-(2-hydroxyethyl)-1H-tetrazol-5-yl-thiol or and pharmaceuticallyacceptable salts thereof. Other useful compounds can be found in U.S.Pat. No. 5,874,455, which is hereby incorporated in its entirety byreference for background information. The above-mentioned chemicals aremerely exemplary and other reducing agents that behave similarly bybreaking the disulfide bond are included within the scope of thisinvention.

The chemical reducing agents can be used alone or in conjunction with acatalyst such as an enzyme. Enzymes and other nutrients suitable forcausing or facilitating reduction include, for example, aldoreductase,glyoxylase, glutathione S-transferase, hexokinase, thiol reductase,thioltransferase, tyrosine reductase or any compatible reductase. Theneed for a source of applied energy for the reduction of the disulfidebonds may be met by the addition of glucose-6-phosphate, which ispresent within the lens but the enzyme, hexokinase that normallyconverts the glucose to the G6P energy state is rendered non-functionalby the process of thiol oxidation. Again, it should be noted that theabove-listed enzymes are exemplary and not an exhaustive list. Theenzymes can be naturally present in the eye, or can be added to the eyetogether with or separate from the chemical reducing agent or energeticmeans disclosed herein. As such, other chemically and biologicallycomparable enzymes that help break disulfide bonds or behave similarlyshould be considered as within the scope of the present invention.

In one embodiment of the invention, the reduction of disulfide groups ofthe lens proteins to sulfhydryl groups is accomplished by delivering tothe lens a compound such as glutathione, thiols, or others in sufficientquantities to reduce the disulfide bonds and other molecular andcellular adhesions. Other enzymes or chemicals that affect a methylationon the free sulfur atom include for example, methyl-methanethiosulfonate, methyl glutathione, S-methyl glutathione, S-transferaseand other biologically compatible methylating agent. Use of emulsionssuch as nanocapsules, albumin microspheres, carrier molecules such asinositol, taurine or other biologically suitable means such as virusphages for delivering the reducing agent or enzymes to the lens is anintegral part of this invention. The chemical reducing agent willtypically be delivered in the form of a solution or suspension in anophthalmically acceptable carrier. In some cases, the application ofenergy to affect or catalyze the reduction of the disulfide bonds aswell as the disruption of other bonds and adhesions may be beneficial.The application of energy alone can be used to break the disulfidebonds. Applied energy can have any form, byway of example only, any oflaser, ultrasound, particle beam, plasma beam, X-ray, ultraviolet,visible light, infrared, heat, ionizing, light, magnetic, microwave,sound, electrical, or other not specifically mentioned, can be usedalone or in combination with the reducing agents to affect the treatmentof presbyopia, or a combination of any of these types of energies.

In a similar manner, agents can be delivered to the lens capsule, whichbind or interact with the capsule to affect greater elasticity ordistensibility. Such agents either cause the capsule to shrink insurface area or increase the tension of the lens capsule on theperipheral anterior or posterior of the lens. Applied energy can haveany form, by way of example only, any of laser, ultrasound, heat,particle beam, plasma beam, X-ray, ultraviolet, visible light, infrared,ionizing, light, magnetic, microwave, sound, electrical, or other notspecifically mentioned can be used alone or in combination with thereducing agents to affect the treatment of presbyopia or a combinationof any of these types of applied energy.

In another embodiment of the invention, applied energy can be used as acatalyst to induce or increase the rate of the reduction reaction. Thus,by applying energy, the peripheral portion of the capsule ispreferentially affected, leaving the central 4 mm zone of accommodationunaffected. This allows the lens to assume a more accommodative state.The applied energy can also be applied alone to promote the reductionreaction and the cellular changes that ultimately affect the lenscortex. As examples, lasers useful in the present invention include:excimer, argon ion, krypton ion, carbon dioxide, helium-neon,helium-cadmium, xenon, nitrous oxide, iodine, holmium, yttrium lithium,dye, chemical, neodymium, erbium, ruby, titanium-sapphire, diode,femtosecond or attosecond laser, any harmonically oscillating laser, orany other electromagnetic radiation. Exemplary forms of heatingradiation include: infrared, heating, infrared laser, radiotherapy, orany other methods of heating the lens. Finally, exemplary forms of soundenergy that can be used in an embodiment of the invention include:ultrasound, any audible and non-audible sound treatment, and any otherbiologically compatible sound energy.

In still another embodiment of the present invention, radiation, such asultraviolet light, visible light, infrared, microwave, or otherelectromagnetic energy may be placed in the eye to help break thedisulfide bonds. This would then make it possible for the reduction ofthe disulfide bonds to occur.

The applied energy used with various embodiments and methods of thepresent invention could be applied through either contact with thesclera or cornea, non-contact techniques, or through intraocular methodsof delivery. More than one treatment may be needed to affect a suitableincrease in the accommodative amplitude. When more than one modality oftreatment is desirable, chemical treatment can be administered prior to,after, or simultaneously with the application of energy.

1. A method of increasing an accommodative amplitude of a lens,comprising: causing a reaction in an eye including: breaking chemicalbonds about lens fibers of the eye; and reducing a likelihood offormation of the chemical bonds; and catalyzing the reaction by applyinga catalyst.
 2. The method of claim 1, wherein breaking comprisesbreaking disulfide bonds to form sulfides.
 3. The method of claim 2,wherein reducing a likelihood of formation comprises reducing thesulfides with an agent to reduce a likelihood of formation of disulfidebonds.
 4. The method of claim 3, wherein the agent is hydrogen.
 5. Themethod of claim 2, wherein reducing a likelihood of formation comprisesreforming sulfide bonds with a molecule.
 6. The method of claim 5,wherein the molecule is —CH3.
 7. The method of claim 1, whereincatalyzing the reaction comprises applying energy.
 8. The method ofclaim 3, wherein catalyzing the reaction comprises applying an agentincluding aldoreductase.
 9. The method of claim 3, wherein catalyzingthe reaction comprises applying an agent including glyoxylase.
 10. Themethod of claim 3, wherein catalyzing the reaction comprises applying anagent including glutathione S-transferase.
 11. The method of claim 3,wherein catalyzing the reaction comprises applying an agent includingthiol reductase.
 12. The method of claim 3, wherein catalyzing thereaction comprises applying an agent including tyrosine reductase. 13.The method of claim 3, wherein catalyzing the reaction comprisesapplying an agent including any biologically suitable compatiblereductase.
 14. The method of claim 1, wherein causing a reactioncomprises applying energy.
 15. The method of claim 1, wherein causing areaction comprises applying an enzyme capable of breaking the chemicalbonds.
 16. The method of claim 15, wherein the enzyme comprises S-methylglutathione.
 17. The method of claim 15, wherein the enzyme comprisesS-transferase.
 18. The method of claim 5, wherein catalyzing thereaction comprises applying a chemical catalyst capable of promoting acatalytic reaction.
 19. The method of claim 18, wherein the chemicalcatalyst comprises methyl-methane thiosulfonate.
 20. The method of claim18, wherein the chemical catalyst comprises methyl glutathione.
 21. Amethod for reversing the effects of presbyopia by applying an externalenergy source to an eye and specifically to a lens of the eye.
 22. Themethod of claim 21 where the energy is of sufficient power to break abond responsible for a loss of flexibility of a presbyopic lens.
 23. Themethod of claim 22 where the energy is of sufficient and correct powerand frequency to cause a harmonic oscillation of the bond.
 24. Themethod of claim 21 where the energy is any form of electromagneticradiation.
 25. The method of claim 21 where the energy is any form ofsound energy.
 26. The method of claim 21 where the energy is any form ofheat.
 27. The method of claim 23 where the bond is a disulfide bond.